Multiple sclerosis (MS) afflicts approximately 400,000 people in the United States and 2.5 million worldwide. MS is an inflammatory disease in which myelin sheaths around the axons of the brain and spinal cord are damaged. In MS as well as other demyelinating diseases, autoimmune inflammatory attack against myelin and oligodendrocytes causes demyelination. The thinning or loss of myelin surrounding axons impairs the ability of the axons to effectively conduct signals and results in progressive neuronal damage.
Remyelination is the process by which new myelin sheaths are generated around axons. Remyelination persists throughout adulthood in the CNS and involves the generation of new myelinating oligodendrocytes (C. Ffrench-Constant, M. C. Raff, Nature, 319, 499 (1986)). Despite controversy regarding their intrinsic in vitro and in vivo lineage potential (M. C. Nunes et al., Nat Med, 9, 439 (2003); S. Belachew et al., J Cell Biol, 161, 169 (2003); T. Kondo, M. Raff, Science, 289, 1754 (2000); Jackson, 2006; Zhu, 2011; Richardson, 2011; R. J. Franklin, C. Ffrench-Constant, Nat Rev Neurosci, 9, 839 (2008)), compelling evidence indicates that a widespread proliferating population of nerve/glial antigen-2 (NG2), platelet-derived growth factor receptor (alpha subunit, PDGFRa) positive cells, termed NG2-glia or oligodendrocyte precursor cells (OPCs), are the major source of newly formed mature oligodendrocytes required for remyelination (P. J. Homer et al., J Neurosci, 20, 2218 (2000); M. C. Nunes et al., Nat Med, 9, 439 (2003); J. M. Gensert, J. E. Goldman, Neuron, 19, 197 (1997); M. S. Windrem et al., Nat Med, 10, 93 (2004); R. J. Franklin, C. Ffrench-Constant, Nat Rev Neurosci, 9, 839 (2008); Richarson, 2011).
Remyelination can occur following the loss of myelin in diseases such as MS, thus restoring neurological function to axons. However, although remyelination can occur in the early stages of MS, oligodendrocytes are unable to completely rebuild the myelin sheath, and repeated inflammatory attacks ultimately lead to fewer effective remyelinations until plaques build up around the damaged axons. A primary cause of remyelination failure is the progressive inability of somatic oligodendrocyte precursor cells to differentiate at the sites of injury. Thus, remission in MS is largely dependent upon OPCs migrating to sites of injury, and subsequently differentiating to a mature cell fate capable of repair (J. R. Patel, R. S. Klein, FEBS Lett, 585, 3730 (2011); D. Kremer et al., Ann Neurol, 69, 602 (2011); A. Chang et al., N Engl J Med, 346, 165 (2002)). Studies aimed at evaluating the presence and relative densities of OPCs at sites of chronically demyelinated MS lesions indicate that it is not a failure of repopulation or migration of OPCs, but rather inhibition of OPC differentiation at sites of injury that contributes to disease progression (D. M. Chari, W. F. Blakemore, Glia, 37, 307 (2002); D. M. Chari et al., J Neurosci Res, 73, 787 (2003); G. Wolswijk, J Neurosci, 18, 601 (1998); A. Chang et al., N Engl J Med, 346, 165 (2002); T. Kuhlmann et al., Brain, 131, 1749 (2008)).
There is no known cure for MS. For treating acute inflammatory attacks, intravenous corticosteroids are typically administered. Other treatments for MS involve the administration of an immunomodulator. Although immunomodulators are able to reduce the frequency and severity of attacks or accumulation of lesions, they do not promote remyelination of damaged axons.